Regioselective One-pot Protection and Protection-glycosylation of Carbohydrates

Deciphering the roles and structure–activity relationships of carbohydrates in biological processes requires access to sugar molecules of confirmed structure and high purity. Chemical synthesis is one of the best ways to obtain such access. However, the synthesis of carbohydrates has long been impeded by two major challenges – the regioselective protection of the polyol moiety of each monosaccharide building block and the stereoselective glycosylation to produce oligosaccharides of desired length. Here, we review the development of the first regioselective protection-glycosylation and a revolutionary regioselective combinatorial one-pot protection of monosaccharides that can be used to differentiate the various hydroxy groups of monosaccharides with a vast array of orthogonal protective groups in one-pot procedures

Yb(OTf)₃‑Catalyzed Desymmetrization of <i>myo</i>-Inositol 1,3,5-Orthoformate and Its Application in the Synthesis of Chiral Inositol Phosphates

A variety of inositol phosphates including <i>myo</i>-inositol 1,4,5-trisphosphate, which is a secondary messenger in transmembrane signaling, were selectively synthesized via Yb­(OTf)₃-catalyzed desymmetrization of <i>myo</i>-inositol 1,3,5-orthoformate using a proline-based chiral anhydride as an acylation precursor. The investigated catalytic system could regioselectively differentiate the enantiotopic hydroxy groups of <i>myo</i>-inositol 1,3,5-orthoformate in the presence of a chiral auxiliary. This key step to generate a suitably protected chiral <i>myo</i>-inositol derivatives is described here as a unified approach to access inositol phosphates

Acyl and Silyl Group Effects in Reactivity-Based One-Pot Glycosylation: Synthesis of Embryonic Stem Cell Surface Carbohydrates Lc₄ and IV²Fuc-Lc₄

Relative reactivity evaluations showed the graded arming of toluenyl thioglucosides by variously positioned silyl groups but not by their acyl counterparts. These findings were applied in reactivity-based one-pot assembly of linker-attached Lc₄ and IV²Fuc-Lc₄, which are components of human embryonic stem cell surface. The sugar–galectin-1 binding was also examined

Glycan sulfation patterns define autophagy flux at axon tip via PTPRσ-cortactin axis

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Microwave-Assisted One-Pot Synthesis of 1,6-Anhydrosugars and Orthogonally Protected Thioglycosides

Living organisms employ glycans as recognition elements because of their large structural information density. Well-defined sugar structures are needed to fully understand and take advantage of glycan functions, but sufficient quantities of these compounds cannot be readily obtained from natural sources and have to be synthesized. Among the bottlenecks in the chemical synthesis of complex glycans is the preparation of suitably protected monosaccharide building blocks. Thus, easy, rapid, and efficient methods for building-block acquisition are desirable. Herein, we describe routes directly starting from the free sugars toward notable monosaccharide derivatives through microwave-assisted one-pot synthesis. The procedure followed the in situ generation of per-<i>O</i>-trimethylsilylated monosaccharide intermediates, which provided 1,6-anhydrosugars or thioglycosides upon treatment with either trimethylsilyl trifluoromethanesulfonate or trimethyl­(4-methylphenylthio)­silane and ZnI₂, respectively, under microwave irradiation. We successfully extended the methodology to regioselective protecting group installation and manipulation toward a number of thioglucosides and the glycosylation of persilylated derivatives, all of which were conducted in a single vessel. These developed approaches open the possibility for generating arrays of suitably protected building blocks for oligosaccharide assembly in a short period with minimal number of purification stages

Divergent Synthesis of 48 Heparan Sulfate-Based Disaccharides and Probing the Specific Sugar–Fibroblast Growth Factor‑1 Interaction

Several biological processes involve glycans, yet understanding their ligand specificities is impeded by their inherent diversity and difficult acquisition. Generating broad synthetic sugar libraries for bioevaluations is a powerful tool in unraveling glycan structural information. In the case of the widely distributed heparan sulfate (HS), however, the 48 theoretical possibilities for its repeating disaccharide call for synthetic approaches that should minimize the effort in an undoubtedly huge undertaking. Here we employed a divergent strategy to afford all 48 HS-based disaccharides from just two orthogonally protected disaccharide precursors. Different combinations and sequence of transformation steps were applied with many downstream intermediates leading up to multiple target products. With the full disaccharide library in hand, affinity screening with fibroblast growth factor-1 (FGF-1) revealed that four of the synthetic sugars bind to FGF-1. The molecular details of the interaction were further clarified through X-ray analysis of the sugar–protein cocrystals. The capability of comprehensive sugar libraries in providing key insights in glycan–ligand interaction is, thus, highlighted

Interactions That Influence the Binding of Synthetic Heparan Sulfate Based Disaccharides to Fibroblast Growth Factor‑2

Heparan sulfate (HS) is a linear sulfated polysaccharide that mediates protein activities at the cell–extracellular interface. Its interactions with proteins depend on the complex patterns of sulfonations and sugar residues. Previously, we synthesized all 48 potential disaccharides found in HS and used them for affinity screening and X-ray structural analysis with fibroblast growth factor-1 (FGF1). Herein, we evaluated the affinities of the same sugars against FGF2 and determined the crystal structures of FGF2 in complex with three disaccharides carrying <i>N</i>-sulfonated glucosamine and 2-<i>O</i>-sulfonated iduronic acid as basic backbones. The crystal structures show that water molecules mediate different interactions between the 3-<i>O</i>-sulfonate group and Lys125. Moreover, the 6-<i>O</i>-sulfonate group forms intermolecular interactions with another FGF2 unit apart from the main binding site. These findings suggest that the water-mediated interactions and the intermolecular interactions influence the binding affinity of different disaccharides with FGF2, correlating with their respective dissociation constants in solution